Atherosclerosis is the leading cause of death and illness in the United States despite all advances in lipid- lowering drugs and lifestyle changes designed to reduce cholesterol levels. Atherosclerosis is a chronic disease that causes accumulation of plaques in the arterial walls. Smooth muscle cells (SMCs) that migrate from the media after phenotypic switching significantly contribute to atherosclerosis and plaque stability. However, the molecular mechanisms responsible for SMC phenotypic modulation in disease development still remain unclear. Consequently, we hypothesize that c-Kit signaling stabilizes the SMC contractile phenotype in arterial walls, which controls the progression of the disease in early atherosclerosis and decreases the risk of plaque rupture in advanced lesions. We support the hypothesis with preliminary studies that demonstrate: 1) the expression of c-Kit in healthy and diseased human and mouse aortas, 2) the role of c-Kit in SMC phenotypic switching, 3) increased systemic atherosclerosis in hyperlipidemic mice with impaired SCF or c-Kit functions, and 4) increased risk for vulnerable plaque rupture in c-Kit deficient mice . We will prove our hypothesis in three specific aims. In aim 1 we propose to test whether c-Kit loss or gain-of-function in SMCs alters atherosclerosis development in hyperlipidemic mice. We will make use of a novel genetically engineered mouse and a newly designed inducible lentivector to inactivate or activate the c-Kit gene in arterial SMCs. In aim 2 we will examine the molecular mechanisms by which c-Kit maintains the contractile phenotype in SMCs. We will use culture cells from c-Kit conditional knockout mice to demonstrate the relevance of the c- Kit/PI3K/Akt signaling axis and DUSP mediated dephosphorylation of MAPK in maintaining the transcription of SMC contractile genes. Finally, in aim 3 we will investigate the impact of altering vascular c-Kit signaling in vascular inflammation and atherosclerotic plaque rupture in vivo. We will evaluate spontaneous plaque rupture in HFD fed conditional mice after tamoxifen feeding to inactivate the c-Kit gene in the plaque. Together, these studies will advance our knowledge about the role of c-Kit in atherosclerosis and will furnish new therapeutic targets to prevent and eventually mitigate the devastating effects of atherosclerosis.